National Institute of Mental Health (NIMH)
National Cancer Institute (NCI)
National Eye Institute (NEI)
National Institute on Aging (NIA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)Eunice
Kennedy Shriver National Institute of Child Health and Human
Development (NICHD)
National Institute on Deafness and Other Communication
Disorders (NIDCD)
National Institute on Drug Abuse (NIDA)
National Institute of General Medical Sciences (NIGMS)

Funding Opportunity Title

Solicitation of Assays for High
Throughput Screening (HTS) to Discover Chemical Probes (R21)

May 30, 2013 (NOT-OD-13-074) -
NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.

January 16, 2013 - See Notice NOT-MH-13-011. The purpose of this notice is to facilitate access for researchers to a screening laboratory to develop an High Throughput Screening (HTS) assay and thereby submit a grant application to this FOA.

This
Funding Opportunity Announcement (FOA) encourages investigators to form
collaborations with an established academic, nonprofit, or commercial high
throughput screening (HTS) facility that has the requisite expertise and
experience to implement HTS-ready assays for the discovery and development of
small molecule chemical probes.

Through this FOA, NIH wishes to stimulate research in 1)
discovery and development of novel, small molecules for their potential use
in studying disease treatment relevant to the missions of the participating
NIH Institutes, and 2) discovery and/or validation of novel, biological
targets that will inform studies of disease mechanisms. Emphasis will
be placed on assays that provide new insight into important disease targets
and processes.

Key Dates

Posted Date

December 13, 2011

Open Date (Earliest Submission Date)

January 5, 2012

Letter of Intent Due Date

30 days prior to the anticipated application due date.

Application Due Date(s)

Standard
dates apply, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Standard
dates apply, by 5:00 PM local time of applicant organization.

Now July 18, 2014. Reissued as
PAR-14-283
(originally September 8, 2014)

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in
the SF
424 (R&R) Application Guide, except where instructed to do otherwise
(in this FOA or in a Notice from the NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the FOA)
is required and strictly enforced. Applicants must read and follow all
application instructions in the Application Guide as well as any
program-specific instructions noted in Section
IV. When the program-specific instructions deviate from those in the
Application Guide, follow the program-specific instructions. Applications that
do not comply with these instructions may be delayed or not accepted for review.

Recent technological innovations in high throughput
screening (HTS), chemical synthesis, and cheminformatics have allowed rapid
discovery of novel, small-molecule probes for the study of disease related
biological processes and mechanisms in academic environments (see Academic
Screening Facilities Directory, http://www.slas.org/screeningFacilities/facilityList.cfm).
This provides an unprecedented opportunity for investigators to translate
knowledge about diseases into tangible tools for translational research. This Funding
Opportunity Announcement (FOA) is to support investigators to form
collaboration with an academic, nonprofit, or commercial HTS screening facility
that has the requisite expertise and experience to implement an HTS-ready assay
for the discovery and development of small molecule chemical probes. Through
this FOA, we wish to stimulate research in 1) discovery and development of
novel, small molecules for their potential use in studying disease treatment
relevant to the missions of the participating NIH Institutes, and 2) discovery
and/or validation of novel, biological targets that will inform studies of
disease mechanisms. Emphasis will be placed on assays that provide new insight
into important disease targets and processes. For example, applications may
involve emerging therapeutic targets and mechanisms for the discovery of
chemical probes that may lead to further development of therapeutics or provide
insight into the biology of relevant diseases.

This program supports mainly the following two stages of
discovery research:

1. HTS implementation. The screening facility should have
the capability to optimize and automate biochemical-, cellular-, or whole
organism-based assays to screen a large library of compounds with adequate
diversity and representation of chemical space. The projects submitted to this
FOA are expected to already have an implementable HTS assay and a large
collection of compounds to be screened. Some assay adaptation may be performed
with the aim of optimizing parameters such as reagent preparation/consumption,
assay readout, and automation in parallel or multiplex screening format. Such
adaptation work will be accomplished through a joint effort between the assay
submitting investigator and the screening facility responsible for implementing
the assays. Some complementary research including biology-oriented chemical synthesis
of screening compounds, virtual screening may also be conducted to improve the
screening success likelihood.

HTS assay development is beyond the scope of the FOA.
Investigators who are interested in the development of HTS assays are
encouraged to apply under PA-10-213 - Development of Assays for High-Throughput screening for use in Probe and
Pre-therapeutic Discovery (R01).

2. Hit validation. When HTS is complete, fresh compound
samples of initial hits will be selected (cherry-picked) for further
confirmation. The investigators will implement secondary assays that are
orthogonal to the primary assay to remove false positives. This provides
additional verification that the hits are acting on the target/pathway of
interest. In addition, the investigators will conduct advanced cheminformatics
analysis and medicinal chemistry inspection to prioritize the hit set. It is
expected that the investigators will test powder samples of hit compounds and
commercially available analog compounds during the hit validation stage. Investigators
should verify the structure of hits using a combination of analytical methods
and, if possible, re-synthesis of select hits. Additional follow-up assays may
also be conducted to characterize mode and mechanism of action of the validated
hits.

A substantial amount of screening campaigns may yield
validated hits that can be further optimized via medicinal chemistry work.
However, extensive medicinal chemistry optimization is beyond the scope of the
FOA. Investigators of a successful screening project are encouraged to
consider further funding opportunities that would support medicinal chemistry
optimization of the validated hits, i.e., PAR-12-060 or other funding opportunities as listed below in the section "Institute
Interests."

Technical
Prerequisites

1. Compound collection. A large library of compounds should
be used for HTS to cover adequate chemical space. In certain cases, it may be
advantageous to utilize focused libraries of compounds with specific
considerations for the assay targets, privileged scaffolds, representative
diversity sets, drug repurposing, and/or the ease of follow-up synthetic
chemistry for SAR expansion. The compounds in such a collection are expected to
be maintained under strict storage conditions and meet a set of quality control
restrictions on purity, solubility, a number of reactive groups, and compound
size.

The application is expected to include preliminary data
on the primary assay performance most often in microtiter plate format (96-,
384- and 1536-well plates). A scatter plot obtained from a pilot screen of a
small collection of structurally diverse small molecules (e.g., NIH Clinical
Collection at http://www.nihclinicalcollection.com/,
LOPAC1280 at http://www.sigmaaldrich.com/chemistry/drug-discovery/validation-libraries.html,
etc.) may provide an overview of the assay performance. An acceptable lower
limit of Z’ factor is 0.5 that corresponds to a combination of Signal-to-Basal
Ratio (S/B) of 4 with a Coefficient of Variation (CV) of 10%.

A Chemical Probe Development Plan (CPDP)
should be developed at the beginning of the project based on the awarded
research application by a team composed of the screening staff, the assay
submitter, and an NIH program staff. The CPDP outlines the projected probe
development path and predicts appropriate benchmarks and timelines.
Importantly, the CPDP defines the specific criteria that a compound must meet
to be considered a probe for the project. The CPDP discussion should include
discussion of prior art of chemical probes, probe definition, assay
responsibilities, hit selection criteria, planned follow-up assays, structure-activity
relationships of bioactive compounds, and a flowchart to summarize critical
path to the probe discovery.

Since an important goal of the NIH is to rapidly
disseminate new and important information, awardees will work together with the
NIH PubChem staff to ensure fidelity of the data (http://pubchem.ncbi.nlm.nih.gov).
Awardees will submit annual Progress Report to summarize the project progress
and data generated in primary HTS assays and follow-up assays.

NIH program staff will review the success of the
screening campaign based on the Progress Report and the PubChem data to
determine feasibility of advancing the project.

Data
Sharing

A goal of the program is to further research advancements
across the scientific community as rapidly as possible. This will require
synergies that can be achieved through broad sharing of research efforts in a
collaborative and cooperative research environment. It will take the
combined resources of researchers in the public and private sectors many years
to use small molecule probes to characterize the biology of genes and proteins
of interest, cellular processes, and disease processes, and then to use that
information to develop products and other approaches that will improve public health.
The open sharing of data, research tools, and resources will not only encourage
scientific rigor in probe discovery process, but also lead more rapidly to the
identification and validation of novel targets for drug discovery, and will
facilitate more rapid development of therapeutics by both the private and
public sectors, with resulting benefits to public health, especially for rare
and neglected disorders. In order to reap the maximum benefit from this
program, assay data, assay protocols, and chemical structures of compounds
tested will be made publicly available.

For the purpose of this FOA, the following data generated or
developed under this FOA are expected to be released to PubChem, consistent
with achieving the goals of this program: (1) primary assay data from high
throughput screening (HTS), (2) data generated in the follow-up assays, (3) protocols
for assays implemented, and (4) the chemical structure of compounds tested.

Applications in response to this FOA should include a
statement of willingness to deposit the aforementioned data to PubChem within the
Data Sharing section of the application.

Project
Oversight

Projects awarded under this FOA are subject to oversight and
review by each of the following entities.

The participating NIH ICs will be responsible for making the
award according to their respective missions to support basic and clinical
research. For each awarded research project, the participating IC will delegate
a program staff to join meeting discussions on the Chemical Probe Development
Plan and participate in coordination of the screening project.

NIH PROJECT TEAM. The NIH Project Team composed of the
participating IC staff will serve as the governing body that oversees the data
deposition to PubChem.

Institute
Interests

NIMH: The NIMH is especially interested in applications for novel,
clinically-relevant targets with the goal of transforming target discovery into
therapeutic treatment of mental disorders such as depressive disorder, bipolar
disorder, schizophrenia, anxiety disorders, panic disorder, and autism, etc. Proposed
projects should be relevant to NIMHs mission of supporting basic science
discoveries and translating these discoveries into new therapeutic
interventions that will relieve the suffering of people with mental disorders. NIMH
encourages cross-disciplinary collaboration among NIMH-funded existing
research, such as Psychopharmacology, Neuropharmacology, Molecular Pharmacology
Research, and Genetic Basis of Mental Disorders Programs. In case a screening
campaign yields promising bioactive hits, investigators are encouraged to
consider the following funding opportunities: Drug Discovery for Nervous System
Disorders PAR-10-001, PAR-10-002,
and Optimization of Small Molecule Probes for the Nervous System PAR-09-251.

NCI:
High throughput screens that are pertinent to the mission of NCI should be
justified in the application as relevant to cancer. The NCI is interested
in high throughput screens intended to identify small molecules for use in
elucidating molecular, cellular, or in vivo mechanisms or processes of probable
or known importance to cancer biology, and for use in developing strategies for
cancer prevention, diagnosis, treatment or clinical monitoring of
treatment. Screens may be biochemical, cellular or model organism-based.
High throughput screens for targets that address unmet needs in cancer
prevention, treatment or diagnosis are encouraged. Validated hits
identified by HTS may be appropriate for entry in the NCI Experimental
Therapeutics Program (NExT) for further development to clinical candidate
status and testing in clinical trial. See http://next.cancer.gov/ for the NExT
application process. Applicants may also find the NCI Developmental
Therapeutics Program (http://dtp.nci.nih.gov)
resources to be helpful.

NEI: The NEI is especially interested in applications to develop novel,
clinically-relevant targets, which can be transformed into therapeutics for
treatment of visual diseases and disorders. Appropriate research areas
include, but are not limited to, inflammatory, vascular, and degenerative
diseases of the eye, such as diabetic retinopathy, age-related macular
degeneration, retinitis pigmentosa, glaucoma, ocular infections, corneal wound
healing, and dry eye syndrome. Proposed projects should be relevant to NEI’s
mission of supporting basic science discoveries and translating these
discoveries into new therapeutic interventions that will lead to sight-saving
treatments, reduce visual impairment and blindness, and improve the quality of
life for people of all ages.

NIA: NIA is interested in HTS assays and chemical probes that are relevant to the
process of normal aging (including normal cognitive aging) and age-related diseases
and conditions in a variety of tissues. Examples include Mild Cognitive
Impairment (MCI), Alzheimer’s disease and other dementias of aging, progeroid
syndromes, osteoporosis, sarcopenia, and other age–related changes that occur
during the human lifespan. NIA is particularly interested in assays
and chemical probes that will be useful in identifying new therapeutic
targets and, novel therapeutic and imaging agents. NIA is also interested in
assays to screen for compounds that affect protective factors or processes that
may contribute to slowing or reversing the progression of age-related adverse
molecular, biochemical, genetic, cellular, or physiological changes that
contribute to multiple age-related diseases, and which hence could contribute
to longer health span.

NIAAA: NIAAA is interested in applications for novel clinically-relevant targets with
the goal of transforming target discovery into treatment of alcohol dependence.
NIAAA is also interested in as the development of novel ligands to be used as
tools for investigating biological processes contributing to alcohol
dependence. Alcohol dependence is a complex disorder involving many
neurotransmitter receptors and transporters, ion channels, neuromodulators,
hormones, and intracellular signaling networks. This provides a number of
potential target sites for which new pharmaceutical agents may be developed.
Examples of interest include: effectors of opioid, glutamate, GABA,
cannabinoid, and adenosine receptors, modulators of neuropeptide systems (e.g.,
NPY, CRF, substance P, orexin), agents that alter signal transduction pathways
(such as protein kinase effectors, protein phosphatase inhibitors, G-protein
regulators and calcium signaling disruptors), and modulators of neuroimmune and
neuroinflammatory pathways. In case a screening campaign yields promising
bioactive hits, investigators are encouraged to consider the following funding
opportunities: Drug Discovery for Nervous System Disorders PAR-10-001, PAR-10-002;
Optimization of Small Molecule Probes for the Nervous System PAR-09-251.

NICHD: NICHD is interested in high throughput screening that will lead to discovery
of chemical probes of developmental targets relevant to pregnancy and
pediatric-related conditions. Potential applicants are encouraged to review the
NICHD mission http://www.nichd.nih.gov/about/overview/mission/ and vision http://www.nichd.nih.gov/vision/ and to contact NICHD program listed on this FOA prior to submitting an
application.

NIDA: NIDA is particularly interested in assays for novel targets that may lead to
the development of pharmacotherapeutics for drug addiction and/or chronic
pain. NIDA is also interested in assays to identify compounds that are
selective for or against reported human genetic or epigenetic variants of known
targets for drug addiction, where the variant is associated with risk for or
protection against dependence or addiction. In case a screening campaign
yields promising bioactive hits, investigators are encouraged to consider the
following funding opportunities: Drug Discovery for Nervous System Disorders PAR-10-001, PAR-10-002;
Optimization of Small Molecule Probes for the Nervous System PAR-09-251.

NIDCD:
The NIDCD is interested in the development of high throughput screens to assess
and identify putative analogs that might have potential therapeutic value in
the treatment, protection or prevention of communication disorders, including
hearing, balance, smell/taste, voice, speech and language. Applications
could include, but are not limited to, identification of clinically-relevant
targets that might lead to translatable therapeutics in hearing/balance areas
of otoprotection, regeneration, otitis media, tinnitus, and normal/abonormal
development; chemosensory abnormalities such as they relate to serious diseases
of obesity, diabetes, Parkinson’s disease, Alzheimer’s disease, and multiple
sclerosis; disorders involving voice speech, language, including swallowing,
aphasia or dysarthria, and laryngeal replacement. Potential
applicants are encouraged to review the NIDCD mission http://www.nidcd.nih.gov prior to
submitting an application.

NIGMS: The NIGMS welcomes assays that are
relevant to the Institute's mission: basic scientific research that increases
understanding of life processes and lays the foundation for more applied advances
in disease diagnosis, treatment, and prevention. NIGMS-funded researchers seek
to answer important scientific questions in fields such as cell biology,
biophysics, genetics, developmental biology, pharmacology, physiology,
biological chemistry, bioinformatics, computational biology, selected aspects
of the behavioral sciences, and specific cross-cutting clinical areas that
affect multiple organ systems.

Section II. Award Information

Funding Instrument

Grant

Application Types Allowed

New
Resubmission
Revision

The OER
Glossary and the SF 424 (R&R) Application Guide provide details on
these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH
appropriations, and the submission of a sufficient number of meritorious
applications.

Award Budget

The total project period for an application submitted
in response to this funding opportunity may not exceed two years. Total direct
costs are limited to $275,000 over an R21 two-year period for each award, with
no more than $200,000 in direct costs allowed in any single year, to cover costs
associated with HTS and post-HTS follow-up assays.

To prevent budget overlap, applicants who will access
assay and chemistry resources at an MLPCN center or other funded resources,
may only request a budget to cover costs outside the funded resources.

Award Project Period

The total project period for an application submitted in
response to this funding opportunity may not exceed 2 years.

NIH grants policies as
described in the NIH Grants
Policy Statement will apply to the
applications submitted and awards made in response to this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA
that is essentially the same as one currently pending initial peer review
unless the applicant withdraws the pending application. NIH will not accept any
application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission
Applications from the SF 424 (R&R) Application Guide.

Section IV. Application and
Submission Information

1. Requesting an
Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1.
Overview Information, prospective applicants are asked to submit a letter
of intent that includes the following information:

The forms package associated with this FOA includes all
applicable components, mandatory and optional. Please note that some
components marked optional in the application package are required for
submission of applications for this FOA. Follow all instructions in the SF424
(R&R) Application Guide to ensure you complete all appropriate “optional”
components.

Page Limitations

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Resource Sharing Plan

Individuals are required to comply
with the instructions for the Resource Sharing Plans (Data Sharing Plan,
Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as
provided in the SF424 (R&R) Application Guide, with the following modifications:

For the purpose of this FOA, the following data generated or
developed under this FOA are expected to be released to PubChem: (1) primary
assay data from high throughput screening (HTS), (2) data generated in the
follow-up assays, (3) protocols for assays implemented, and (4) the chemical
structure of compounds tested.

Responses to this FOA should include a statement of willingness
to deposit the aforementioned data to PubChem within the Data Sharing section
of the application.

Appendix

Do not use the Appendix to
circumvent page limits. Follow all instructions for the Appendix as described
in the SF424 (R&R) Application Guide.

Foreign Institutions

Foreign (non-US) institutions must follow policies described
in the NIH
Grants Policy Statement, and procedures for foreign institutions described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in
advance of the deadline to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants
across all Federal agencies. Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants
administration.

Applicants
are responsible for viewing their application in the eRA Commons to ensure accurate
and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the SF
424(R&R) Application Package. Failure to register in the Commons and
to include a valid PD(s)/PI(s) Commons ID in the credential field will prevent
the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review, NIH. Applications that are
incomplete will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact

Reviewers will provide an overall impact/priority score to
reflect their assessment of the likelihood for the project to exert a
sustained, powerful influence on the research field(s) involved, in
consideration of the following review criteria and additional review criteria
(as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field? Are there important and well-defined goals
for the use of chemical probes identified with the proposed assays, either as
research tools or for therapeutics development?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD(s)/PI(s), do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project? Are the investigators reasonably knowledgeable and experienced about the biological target
area of science? Are the investigators reasonably knowledgeable and experienced
about assay implementation and the process of screening compound libraries? Are
the investigators reasonably knowledgeable and experienced to conduct follow-up
assays to validate screening hits? Are the investigators reasonably
knowledgeable to examine non-specific chemical reactivity and interference of
compounds?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed? Is this assay project for a novel biological target or cellular process? Does the application address
whether or not there are known small molecule modulators available for this
biological target? Is there a need for better small molecule modulators against
the target or cellular process? Will the innovation in assay design and
compound assembly lead to better success likelihood of the screening?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be
managed?

If the project involves clinical research, are the plans for 1) protection of human
subjects from research risks, and 2) inclusion of minorities and members of
both sexes/genders, as well as the inclusion of children, justified in terms of
the scientific goals and research strategy proposed?

Is the compound library adequate for screening? Is
the HTS assay well designed to minimize false positives and false negatives? Is
there sufficient preliminary data to support assay readiness for HTS? Is there
an assay performance parameter calculated, such as Z'-factor? Is the assay
reproducible? Are non-commercial reagents required for this assay? If so, how
are they characterized for purity and activity, and are they readily available?
Are there adequate data and plan for secondary and tertiary follow-up assays to
evaluate active compounds identified in the primary assays?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact/priority score, but will
not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the
application as now presented, taking into consideration the responses to
comments from the previous scientific review group and changes made to the
project.

Renewals

Not Applicable.

Revisions

For Revisions, the committee will consider the
appropriateness of the proposed expansion of the scope of the project. If the Revision
application relates to a specific line of investigation presented in the
original application that was not recommended for approval by the committee,
then the committee will consider whether the responses to comments from the
previous scientific review group are adequate and whether substantial changes
are clearly evident.

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact/priority score.

Applications from Foreign
Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact/priority
score.

Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications
will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications
will receive a second level of review by the appropriate National Advisory Council or Board. The following will be considered in making funding
decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD(s)/PI(s) will be able to access his or her Summary Statement (written
critique) via the eRA Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH Grants
Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.